Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0043—Nose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof

Definitions

• the present patent application relates to a fixed dose pharmaceutical composition comprising mometasone and azelastine.
• the present patent application provides a stable fixed dose pharmaceutical composition in the form of a nasal spray comprising mometasone or its salt and azelastine or its salt; a process for preparing such composition; and its use in treatment of rhinitis in a subject.
• Rhinitis is a medical term for irritation and inflammation of the mucous membrane inside the nose. Rhinitis may cause additional symptoms, such as sneezing and nasal itching, coughing, headache, fatigue, malaise, and cognitive impairment.
• Mometasone furoate is a glucocorticosteroid used topically to reduce inflammation of the skin or in the airways. It is a prodrug of the free form, mometasone. Mometasone furoate is commercially available as NASONEX ® (marketed by Schering) as a nasal spray for upper respiratory conditions such as nasal sinus inflammation. It is approved for the treatment of nasal symptoms of allergic rhinitis, nasal congestion associated with seasonal allergic rhinitis, nasal polyps and prophylaxis of seasonal allergic rhinitis.
• NASONEX ® (mometasone furoate nasal spray) Nasal Spray 50 meg is a metered- dose, manual pump spray unit containing an aqueous suspension of mometasone furoate monohydrate equivalent to 0.05% w/w mometasone furoate calculated on the anhydrous basis; in an aqueous medium containing glycerin, microcrystalline cellulose and carboxymethylcellulose sodium, sodium citrate, citric acid, benzalkonium chloride, and polysorbate 80.
• the pH is between 4.3 and 4.9.
• Azelastine is ( ⁇ )-l-(2H)-phthalazinone, 4-[(4-chlorophenyl) methyl]-2- (hexahydro-1 -methyl- lH-azepin-4-yl)-, monohydrochloride.
• Azelastine hydrochloride is commercially available in the US as ASTELIN® (azelastine hydrochloride) Nasal Spray, 137 micrograms (meg), is an antihistamine formulated as a metered-spray solution for intranasal administration.
• ASTELIN® Nasal Spray contains 0.1% azelastine hydrochloride in an aqueous solution at pH 6.8 ⁇ 0.3.
• each metered spray delivers a 0.137 mL mean volume containing 137 meg of azelastine hydrochloride (equivalent to 125 meg of azelastine base).
• European Publication No EP0780127A1 discloses a pharmaceutical composition
• a pharmaceutical composition comprising (a) a glucocorticoid selected from the group consisting of beclomethasone, flunisolide, triamcinolone, fluticasone, mometasone, budesonide, pharmaceutically acceptable salts thereof and mixtures thereof; (b) a leukotriene inhibiting antihistamine selected from the group consisting of cetirizine, loratadine, azelastine, pharmaceutically acceptable salts thereof, optically active racemates thereof and mixtures thereof; and (c) an intranasal carrier.
• a glucocorticoid selected from the group consisting of beclomethasone, flunisolide, triamcinolone, fluticasone, mometasone, budesonide, pharmaceutically acceptable salts thereof and mixtures thereof
• a leukotriene inhibiting antihistamine selected from the group consisting of cetirizine,
• European Publication No EP2072051A1 discloses a pharmaceutical composition comprising azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and mometasone or a pharmaceutically acceptable ester thereof.
• PCT Publication No. WO2012074231 discloses a pharmaceutical composition including mometasone furoate and azelastine hydrochloride for nasal administration, including thaumatin as a bitterness and irritation mitigant.
• the present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray that includes mometasone and azelastine.
• the present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray comprising effective amount of mometasone or its salt and azelastine or its salt.
• the present invention relates to a fixed dose pharmaceutical composition
• a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
• the pharmaceutical composition comprises mometasone or its salt is present in an amount from about 0.05 % to about 1 % by weight.
• the pharmaceutical composition comprises azelastine or its salt is present in an amount from about 0.1 % to about 1 % by weight.
• the present invention relates to a fixed dose pharmaceutical composition
• a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt in a weight ratio ranging from about 1: 1 to about 1:5 and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
• each spray of the composition delivers about 50 meg of mometasone furoate and about 140 meg of azelastine hydrochloride.
• the present invention relates to a fixed dose pharmaceutical composition
• a fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
• the present invention relates to a fixed dose pharmaceutical composition
• a fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride and neotame, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
• the present invention relates to a the fixed dose pharmaceutical composition
• a the fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and an excipient selected from the group consisting of carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, or mixtures thereof.
• the present invention relates to a stable fixed dose pharmaceutical composition
• a stable fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, and water, wherein the composition is administered as one spray per nostril twice daily to a subject in need thereof.
• the stable fixed dose pharmaceutical composition of the present invention has pH in the range of about 4.0 to about 5.0, Osmolality in the range of about 270 mOsm to about 370 mOsm, viscosity in the range of about 50 cPs to about 100 cPs and weight per ml in the range of about 0.90 g/ml to about 1.20 g/ml.
• the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
• the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
• the present invention relates to a method of relief of nasal and non-nasal symptoms associated with rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
• the present invention relates to a method of treating rhinitis in a subject by reducing the nasal and non-nasal symptoms associated with rhinitis (such as sneezing, nasal itching, rhinorrhea, nasal obstruction, ocular pruritis, excess lacrimation and the like) in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
• nasal and non-nasal symptoms associated with rhinitis such as sneezing, nasal itching, rhinor
• Rhinitis in the context of present invention includes, but is not limited to, irritation and inflammation of the mucous membrane inside the nose and nasal and non- nasal symptoms associated therewith. It includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, infective rhinitis, autonomic rhinitis, hormonal rhinitis, drug-induced rhinitis, atrophic rhinitis, and gustatory rhinitis.
• the nasal and non-nasal symptoms associated with rhinitis include sneezing, nasal itching, rhinorrhea (runny nose), nasal obstruction, coughing, ocular pruritis, excess lacrimation, headache, fatigue, common cold (also known as nasopharyngitis, rhinopharyngitis, acute coryza, or cold), malaise and cognitive impairment.
• an effective amount denotes an amount of an active ingredient that, when administered to a subject for treating rhinitis, produces an intended therapeutic benefit in a subject.
• active ingredient (used interchangeably with “active” or “active substance” or “drug”) as used herein includes mometasone, azelastine or a pharmaceutically acceptable salt thereof.
• salts and esters are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
• Representative acid additions salts include the hydrochloride, furoate, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts.
• Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.
• treating also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by the mometasone or azelastine, or by a combination of the two in a mammal.
• subject includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
• the subject is a human.
• pharmaceutically acceptable excipients any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
• the therapeutically effective amount of mometasone (or its pharmaceutically acceptable salt) to be administered per day may range from about 100 meg to about 500 meg, preferably from about 200 meg to about 400 meg.
• the discrete dosage strengths of mometasone (or its pharmaceutically acceptable salt) may be about 25 meg, about 50 meg, about 75 meg and about 100 meg.
• the therapeutically effective amount of azelastine (or its pharmaceutically acceptable salt) to be administered per day may range from about 300 meg to about 2000 meg, preferably from about 500 meg to about 1800 meg.
• the discrete dosage strengths of azelastine (or its pharmaceutically acceptable salt) to be administered per day may be about 100 meg, about 125 meg, about 140 meg, about 150 meg, about 200 meg, about 275 meg, about 300 meg and about 500 meg.
• the present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray that includes mometasone and azelastine.
• the present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray comprising effective amount of mometasone or its salt and azelastine or its salt.
• a specific dosing regimen i.e., one spray per nostril twice daily
• the other dosing regimen i.e., two sprays per nostril once daily
• the present invention relates to a fixed dose pharmaceutical composition
• a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
• the pharmaceutical composition comprises mometasone or its salt is present in an amount from about 0.05 % to about 1 % by weight.
• the pharmaceutical composition comprises azelastine or its salt is present in an amount from about 0.1 % to about 1 % by weight.
• the present invention relates to a fixed dose pharmaceutical composition
• a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt in a weight ratio ranging from about 1: 1 to about 1:5 and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
• each spray of the composition delivers about 50 meg of mometasone furoate and about 140 meg of azelastine hydrochloride.
• the present invention relates to a fixed dose pharmaceutical composition
• a fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
• the present invention relates to a fixed dose pharmaceutical composition
• a fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride and neotame, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
• the present invention relates to a the fixed dose pharmaceutical composition
• a the fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and an excipient selected from the group consisting of carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, or mixtures thereof.
• the present invention relates to a stable fixed dose pharmaceutical composition
• a stable fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, and water, wherein the composition is administered as one spray per nostril twice daily to a subject in need thereof.
• the stable fixed dose pharmaceutical composition of the present invention has pH in the range of about 4.0 to about 5.0, Osmolality in the range of about 270 mOsm to about 370 mOsm, viscosity in the range of about 50 cPs to about 100 cPs and weight per ml in the range of about 0.90 g/ml to about 1.20 g/ml.
• the pharmaceutical composition includes at least one pharmaceutically acceptable excipient, which includes but is not limited to one or more of the following; preservatives, buffering agents, chelating agents, polymers, surfactants, sweeteners, solvents and the like.
• buffering agents may be selected from, but not limited to phosphate, borate, sodium citrate and other organic acids like citric acid; carbohydrates dextrose, mannose, or dextrins and the like.
• suitable water soluble polymers may be selected from, but not limited to polyhydroxy alcohols such as glycerin, polyethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 2-methyl-2,4-pentanediol, 1,2,6-hexanetriol and thioglycol, alginic acid, polyoxyethylene polyoxypropylene glycol, pectin, low methoxyl pectin, guar gum, gum arabic, carrageenan, cellulose derivatives such as carmellose sodium, methyl cellulose, carboxymethyl cellulose sodium, xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or mixtures thereof.
• polyhydroxy alcohols such as glycerin, polyethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 2-methyl-2,4-pentanediol, 1,2,6-hexanetriol and
• the above polyoxyethylene polyoxypropylene glycol is a series of polymers in which ethylene oxide has been addition-polymerized to a polypropylene glycol obtained by polymerization of propylene oxide, and are classified into several types by the difference in the mean degree of polymerization of propylene oxide and ethylene oxide.
• Particularly preferred water soluble polymers are polyhydroxy alcohols such as polyethylene glycol, propylene glycol, glycerol and cellulose derivatives such as hydroxypropyl methyl cellulose.
• the amount of water soluble polymer may ranges from about 0.001% to about 30% w/w relative to the total weight of the solution.
• Suitable surfactants which can be used may include one or more of anionic, cationic, non-ionic or zwitterionic surfactants.
• Suitable surfactants may be selected from, but not limited to polyethoxylated sorbitan derivatives such as polysorbates, their ether ethoxylates, produced by reaction of sorbitan esters with ethylene oxide, polyoxyethylene alkyl phenol, polyoxyethylene cetyl ether, polyoxyethylene alkyl-aryl ether, polyoxyethylene monolaurate, polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene esters or mixed fatty and resin acids, polyoxyethylene sorbitol lanolin derivative, polyoxyethylene tridecylether, polyoxyethylene sorbitan esters of mixed fatty and resin acids, polyethoxylated sorbitan derivatives or esters of fatty acids (e.g., polyethoxylated sorbitan derivatives such as polysorbates, their ether ethoxylates, produced by reaction of sorbitan esters with ethylene oxide, polyoxyethylene alkyl phenol, polyoxyethylene cetyl ether, polyoxy
• Polysorbates polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether, polyoxyethylene fatty alcohol, polyoxyethylene alkyl amine, polyoxyethylene glycol monopalmitate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene cetyl ether, polyoxyethylene oxypropylene stearate, polyoxyethylene lauryl ether, polyoxyethylene lanolin derivative, sodium oleate, quaternary ammonium derivative, potassium oleate, N-cetyl N-ethyl morpholinium ethosulfate, sodium lauryl sulfate or mixtures thereof.
• Particularly preferred surfactants are polyethoxylated sorbitan derivatives.
• preservatives examples include, but not limited to benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, disodium edetate. Quaternary ammonium halide preservatives are preferred. Suitable quaternary ammonium halide preservatives include polyquaternium- 1 and benzalkonium halides. Preferred benzalkonium halides are benzalkonium chloride and benzalkonium bromide.
• chelating agents which can be employed may be selected from, but not limited to edetate disodium (EDTA); edetate trisodium; edetate tetrasodium; and diethyleneamine pentaacetate, preferably EDTA.
• EDTA edetate disodium
• edetate trisodium edetate trisodium
• edetate tetrasodium edetate tetrasodium
• diethyleneamine pentaacetate preferably EDTA.
• suitable sweeteners which can be employed may be selected from, but not limited to sucralose, sucrose, saccharin, fructose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor.
• suitable solvents are all solvents which are suitable for nasal administration, in particular water and alcohols, such as, for example, ethanol, propanol, propanediol or glycerol.
• the optimal dose of the active ingredient or the combination of the active ingredients can vary as a function of the severity of disease, route of administration, composition type, the patient body weight, the age and the general state of mind of the patient, and the response to behavior to the active ingredient or the combination of the active ingredients.
• compositions according to the present invention can comprise insufflation powder formulations, nasal sprays, nasal inhalation solutions or aerosols substantially as hereinbefore described.
• the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
• the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
• each spray of the composition delivers about 50 meg of mometasone furoate and about 140 meg of azelastine hydrochloride.
• the present invention relates to a method of relief of nasal and non-nasal symptoms associated with rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
• the present invention relates to a method of treating rhinitis in a subject by reducing the nasal and non-nasal symptoms associated with rhinitis (such as sneezing, nasal itching, rhinorrhea, nasal obstruction, ocular pruritis, excess lacrimation and the like) in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
• nasal and non-nasal symptoms associated with rhinitis such as sneezing, nasal itching, rhinor
• Rhinitis in the context of present invention includes, but is not limited to, irritation and inflammation of the mucous membrane inside the nose and nasal and non- nasal symptoms associated therewith. It includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, infective rhinitis, autonomic rhinitis, hormonal rhinitis, drug-induced rhinitis, atrophic rhinitis, and gustatory rhinitis. Preferably, it includes allergic rhinitis, perennial rhinitis, persistent rhinitis, seasonal rhinitis and nasal and non-nasal symptoms associated therewith.
• the nasal and non-nasal symptoms associated with rhinitis include sneezing, nasal itching, rhinorrhea (runny nose), nasal obstruction, coughing, ocular pruritis, excess lacrimation, headache, fatigue, common cold (also known as nasopharyngitis, rhinopharyngitis, acute coryza, or cold), malaise and cognitive impairment.
• EXAMPLE 1 Compositions of mometasone and azelastine for nasal administration.
• Glycerin/ Dextrose was dissolved in purified water. Sifted microcrystalline cellulose- carboxymethyl cellulose sodium and carmellose sodium were dispersed in the above solution under homogenization.
• Azelastine hydrochloride was dissolved in purified water under stirring and neotame was added under homogenization. This solution was added to step 2 under homogenization.
• Disodium edetate was dissolved in purified water under stirring and added to step 4 under homogenization.
• Benzalkonium Chloride was dissolved in purified water under stirring and added to step 5 under homogenization.
• the pH was adjusted with 10 % citric acid solution and the volume was made up with purified water.
• composition was homogenized and filled in container suitable for nasal administration.
• the composition was subjected to stability studies at different conditions. The results of the same are as follows:
• EXAMPLES 2 - 5 Compositions of mometasone and azelastine for nasal administration.
• Citric acid 0.0150 0.0150 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0
• EXAMPLE 6 Multicenter, Open-Label, Randomized, Parallel-Group, Comparative Study To Evaluate Efficacy, Safety and Tolerability of Fixed Dose Combination of Azelastine and Mometasone Nasal Spray Compared to Azelastine Nasal Spray and Mometasone Nasal Spray in Patients with Seasonal Allergic Rhinitis.
• nasal congestion severity score must be at least 2 at screening.
• Study Duration for Each Patient Total study duration was 15 to 18 days. This included screening period, 14 days active treatment period and allowable window period for the study visits. Investigational Product, Dosage and Mode of Administration:
• TEST 1 (Tl): Fixed Dose Combination of Azelastine hydrochloride 140 meg and Mometasone furoate 50 meg Nasal Spray (as in Example 1). The dose administered was
• TEST 2 Fixed Dose Combination of Azelastine hydrochloride 140 meg and Mometasone furoate 50 meg Nasal Spray (as in Example 1). The dose administered was
• REFERENCE 1 (Rl): Azelastine hydrochloride Nasal Spray (lmg/ml) (RINOLASTIN, ACHE PHARMACEUTICALS). The dose was 1 spray per nostril twice daily for two weeks.
• R2 Mometasone furoate 50 meg Nasal Spray (NASONEX, SCHERING-PLOUGH). The dose was 2 sprays per nostril once daily for two weeks.
• the primary efficacy variable was mean change in Total Nasal Symptoms Score (TNSS, sum of scores of Nasal Congestion, Rhinorrhea, Itching and Sneezing) from Baseline to End of treatment (two weeks).
• TNSS Total Nasal Symptoms Score
• Rhinoconjunctivitis Quality-of-Life Score ⁇ questionnaire containing 28 items in seven domains (Activity, Sleep, Nose Symptoms, Eye Symptoms, Non- Nose/Eye Symptoms, Practical Problems and Emotional Functions) ⁇ from Baseline to End of treatment (two weeks).
• All Patients enrolled in the trial were randomized in 1: 1: 1: 1 to receive either the 1 spray per nostril twice daily of Fixed Dose Combination of Azelastine 140 meg and Mometasone 50 meg Nasal Spray or 2 sprays per nostril once daily of Fixed Dose Combination of Azelastine 140 meg and Mometasone 50 meg Nasal Spray or 1 spray per nostril twice daily of Azelastine Nasal Spray (lmg/ml) or 2 sprays per nostril once daily of Mometasone 50 meg Nasal Spray.
• the study medications were given for fourteen days.
• TNSS Total Nasal Symptoms Score
• TNSS is sum of scores of Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing.
• TNSS at Baseline visit Morning TNSS of Baseline visit (Day 1) + Evening TNSS of day prior to baseline visit (Day 1).
• TNSS at End of Treatment Average of Morning TNSS for Day 2 to Day 15 + Average of Evening TNSS for Day 1 to Day 14.
• TNSS Total Nasal Symptoms Score
• p-value is calculated for the comparison of baseline and end of treatment values within each treatment group by using paired t-
• TNSS Total Nasal Symptoms Score
• the LS means, standard error, 95% confidence intervals are using ANCOVA with treatment and centre as factors and baseline data as covariate.
• p-value is calculated for the pair wise comparison between each of the FDC Nasal Spray versus each of the monotherapy Nasal Spray by using ANCOVA.
• Tl i.e., one spray per nostril twice daily
• T2 i.e., two sprays per nostril once daily
• Tl i.e., one spray per nostril twice daily
• dosing regimen is a preferred dosing regimen for treating allergic rhinitis in a subject.

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